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Thread: $64,000 question

  1. #1

    $64,000 question

    DA has asked us all how we think research is going - Wise I would like to ask you whether research is in a good position at the start of 2004?

  2. #2
    We should be asking ourselves what problems need to be solved to achieve a cure. These problems exist on several levels, both scientific and societal. Let me address the scientific ones first and then the societal ones.

    Scientific.
    Bridging the injury site. The injury site is not hospitable to growing axons. One of the most promising approaches to this problem is to transplant cells that can bridge the injury site so that axons can grow across. In the last five years, several centers have achieved routine transplantation of a variety of cells into injured human spinal cord. These cells include human fetal spinal cords, pig fetal stem cells, human fetal olfactory ensheathing glia, human adult olfactory ensheathing glia cultivated from the nasal mucosa, and human adult mucosa into the spinal cord of chronic injured spinal cords. The safety of the transplantation procedure is well established. To my knowledge, none of the patients have died or gotten worse (although we should not be surprised that there will be some mortality after so many surgeries). On the other hand, none of the patients have shown dramatic recovery that anybody would consider a "cure". Animal studies have suggested that adult and fetal olfactory ensheathing glia, embryonic stem cells, and fetal neural stem cells may have beneficial effects on injured rat spinal cords. Two clinical cell transplantation trials have taken place in the United States. But clinicians do not have access to embryonic stem cells or fetal cells for transplantation. We must find a feasible source of cells for transplantation. At the present, fetal olfactory ensheathing glial cells appear produce a modest improvement of function but that source of cells would be very difficult to establish in the United States. In my opinion, olfactory ensheathing glia are currently are most promising approach to bridging the spinal cord and therefore my laboratory is focusing on these cells.
    Growth factors. We need to "kickstart" axonal growth in chronically injured spinal cords and maintain their growth over long distances. The good news is that many studies with peripheral nerve insertion into the spinal cord (in animals and humans) indicate that if you provide axons a path to grow, they will take it and grow all the way. Recent animal studies have shown many growth factors that to stimulate axonal growth. For example, combination neurotrophins and drugs that increase cAMP appear to stimulate functional regeneration in animals. Chondroitinase was recently reported to improve regeneration and locomotor recovery in the spinal cord. Some growth factors, such as GDNF, appear to recruit more axons to grow into cellular bridges. However, animal studies (and some human studies) suggest that growth factors alone may not sufficient to stimulate regeneration and recovery of function in contusion models of spinal cord injury (the most common form of human spinal cord injury). A very recent study (soon to be published) from the Miami Project suggests that the combination of Schwann cell transplants and rolipram (a drug that increases cAMP levels in the spinal cord) significantly stimulates regeneration and markedly improves locomotor recovery in rats after spinal crod injury. So, I think that there is a need to combine growth factor treatment with cell transplants. Many laboratories are beginning to assess combination of cell transplant and growth factors. We should anticipate several positive reports of combination therapies coming out in 2004.
    Stem cells to replace neurons. Injury not only disrupts axons but also kills neurons in the immediate vicinity of the injury. The great promise of stem cells is that they may be able to produce new neurons in the spinal cord to replace those that have been lost. In the next few months, we will probably see several reports that embryonic or fetal stem cells can produce new neurons that are functional in injured spinal cords. Unfortunately, we are again facing the problem of suitable source of stem cells for clinical trials. Political decisions at the very top of our government have essentially shut down embryonic stem cells as a source. While there may be stem cells in bone marrow, umbilical cord blood stem cells, and neural stem cells from adult brain and spinal cord, we currently do not have reliable methods of isolating these stem cells. At least one center (University of Sao Paolo in Brazil) has been transplanting bone marrow cells into chronic injured human spinal cord. Umbilical cord blood cells may represent another feasible and fundable source of cells. At Rutgers, Ira Black is focusing on animal studies of bone marrow stem cells while we at the Keck Center have begun studying umbilical cord blood cells in spinal cord contusion models.

    Societal barriers
    Clinical trial funding. We currently have minimal governmental or industry funding for spinal cord injury clinical trials. Efforts to pass the Christopher Reeve Paralysis bill in Congress to encourage NIH to spend about $300 million to establish clinical centers to test therapies have been blocked for nearly 2 years. The commitment is simply not there in Congress to provide even this minimal funding for clinical trials. The establishment of half a dozen clinical trial centers aiming at therapies to reverse paralysis would go a long ways to reducing the costs of clinical trials in the United States and would encourage the pharmaceutical industry to invest as well.
    Pessimism of Clinicians. Many clinicians continue to be skeptical about the possibility that any therapy will restore function to people with chronic spinal cord injury. While there are spots of hope in a few centers, most of the clinical trial activity is going on overseas. We need several clinical trial successes to turn the heads of most clinicians and obtain the momentum to convince clinicians to buy into the idea of clinical trials. The FDA may approve of 4-AP for chronic spinal cord injury. If so it will be the first therapy approved by the FDA for restoring function in chronic spinal cord injury. This will help but we need several more victories.

    I believe that all the above problems are potentially solvable but it will take a lot of hard work, collaboration, and some luck to solve all of these problems within a year. I believe that 2004 will be a banner year for spinal cord injury research and that we will achieve significant progress in 2004, more than 2003. Does this mean that we will have a therapy within the year that will restore function to humans with chronic spinal cord injury? I don't know. Probably not within the year, given the considerable political obstacles to establishing a feasible source of cells for clinical transplantation, the lack of significant funding for clinical trials, and the continued skepticism on the part of the clinicians. Will it happen in 2005? It is possible. Much depends on continued progress in the laboratory in finding a feasible source of cells for transplantation and how the combination therapy studies are going. That part of the crystal ball is still foggy to me.

    Wise.

    [This message was edited by Wise Young on 01-04-04 at 05:04 PM.]

  3. #3
    Senior Member Rollin Rick's Avatar
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    Thank you for the great information Dr. Wise. You just won $64,000, lol. Let's just hope that things go our way, thanks again.

    What one man can do another can do

  4. #4
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    Thanks, Dr. Young. You are an amazing individual from everything I've read. I can't believe I never stumbled across CareCure before a few weeks ago--it's a phenomenal resource.

    Regards,
    Sue

  5. #5
    Senior Member Schmeky's Avatar
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    Dr. Young,

    I as well as many others are aware of the obstacles that must be overcome, just as you mentioned in this post. I believe you have more insight into the overall SCI picture than anyone else.

    You stated that effective therapies could "possibly" emerge in 2005. What do feel would be the chances of effective therapies being available up to and including the year 2010?

    Fair, good, very good, or a certainty?

    Some board members may criticize 2010 but there are many hurdles to overcome and they take lots of time and money.

  6. #6
    Senior Member DA's Avatar
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    Does this mean that we will have a therapy within the year that will restore function to humans with chronic spinal cord injury? I don't know. Probably not within the year, given the considerable political obstacles to establishing a feasible source of cells for clinical transplantation, the lack of significant funding for clinical trials, and the continued skepticism on the part of the clinicians.


    do we not already have therapies restoring function to the chronic spinal cord injury?
    it may not be much function.

  7. #7
    The cure requires hard work, resources, and luck. The first I can predict. The second we can work on. The third is unfortunate but true. Every clinical trial is a gamble because there are too many unknowns in the equation to predict the outcome. Due to our limited resources, we cannot afford too many tries. Therefore, we must make every clinical trial a slam-dunk. Wise.

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